PROJECT SUMMARY About 80% of individuals with a moderate to severe ischemic stroke suffer from upper extremity motor impairment, particularly affecting the wrist and fingers. Wrist/finger weakness in these individuals is greater for extensors than flexors, causing difficulty in hand opening, and leading to a dysfunctional wrist/finger flexed posture. Moreover, more severely impaired individuals involuntarily close the hand when attempting to open. Previous neuroimaging studies of this impairment have reported increased neural activity in motor cortices of both lesioned and contralesional hemispheres in these individuals during hand movements. It is also found that the more severe the stroke, the greater activity in the contralesional hemisphere compared to the ipsilesional (i.e. shift of activity to non-lesioned hemisphere). It remains unclear, however, which motor pathways allow the contralesional motor cortex to control the ipsilateral paretic arm in these individuals, therefore leading to a preserved ability for wrist/ fingers flexion and restrained extension. One proposed explanation for the contralesional cortical hyperactivity in individuals with stroke could be an increased reliance on ipsilateral brainstem motor pathways from the spared hemisphere. Furthermore, animal studies have shown that stimulation of reticulospinal tract nuclei in brainstem causes limb flexion in elbow, wrist and fingers. Given this information, I hypothesize that relative preservation to flex and limitation to extend hand/fingers post stroke is the result of greater reliance on indirect contralesional cortico-reticulospinal pathways following damage to the corticospinal pathway in the lesioned hemisphere. Corticospinal and cortico-reticulospinal tracts pass through the same regions in the brain, but completely separate areas in pons, medulla and spinal cord. The overall aim of this proposal, therefore, is to test the activity in reticulospinal tract nuclei in brainstem, as well as the structural changes in reticolospinal and corticospinal tracts in brainstem and spinal cord. Activation in brainstem reticulospinal tracts nuclei will be determined in individuals with stroke compared to controls using fMRI during hand opening and closing tasks, while recording hand movement kinematics and grasping force as well (Aim 1). Given the fact that neural activity changes over the time lead to morphological changes, high resolution anatomical MRI and DTI (diffusion tensor imaging) will be also used to identify the morphological changes in corticospinal and reticulospinal tracts in brainstem (Aim2a). Finally, to reconfirm morphological changes more caudally, white matter integrity of corticospinal and reticulospinal tracts will be quantified at the cervical spinal cord in individuals with stroke and in controls (Aim2b). Findings from the proposed work will elucidate motor pathways involved in hand dysfunction post stroke and facilitate the development of more effective therapeutic interventions post stroke.